Purpose:
Age-related macular degeneration (AMD) is the leading cause of blindness among the adult population in the developed world. In this study we examined how the complement factor related genes CFHR1 and CFHR3 deletion polymorphisms modulate risk of AMD in both an Amish and non-Amish population.

Methods:
The Amish sample included 65 cases and 616 controls. The non-Amish Caucasian comparison sample included 582 cases and 297 unrelated controls. Copy number was assessed using Taqman targeting the CFHR1/CFHR3 common deletion polymorphism. Results of the copy number assay were exported to R for analysis. For the non-Amish sample, a logistic regression was carried out correcting for age at time of examination and smoking status. To correct for the relatedness of the Amish population, case-control association analysis with adjustment for relatedness based on the complete 13-generation pedigree was carried out using MQLS.

Results:
We identified a significant protective effect of the CFHR1 and CFHR3 deletion polymorphism (p < 0.0001, OR= 0.35; 95% CI [0.23 - 0.54]) with AMD in the non-Amish sample. In the Amish dataset, an unadjusted chi-square analysis also generated a highly significant protective effect of the deletion polymorphism with AMD (p < 0.0001, OR=0.32; 95% CI [0.18 - 0.56]). However, when correcting for relatedness, the trend is the same but the effect is no longer significant.

Conclusions:
In this analysis we observed a significant protective effect of the CFHR1 and CFHR3 deletion polymorphism in our non-Amish sample. This same association is not significant in the Amish dataset when correcting for relatedness. This lack of significance is likely due to the relatively small sample size. Upon examination of the CFHR1 and CFHR3 deletion allele frequency in the Amish sample before and after adjustment for relatedness, we observe a clustering of alleles within sibships in the controls whereas no such clustering is seen among the cases. This suggests that there is a possible aggregation of alleles in one section of the Amish pedigree and that the polymorphism is not segregating uniformly throughout the entire Amish sample.